Oral alkyl glycerol ether improvement in radiation,radiomimetic,or cytostatic tumor therapies



United States Patent 7 Claims Int. Cl. A61k 27/00 ABSTRACT OF THEDISCLOSURE An improvement in the use of alkyl glycerol ethers inconjunction with radiation therapy in the treatment of tumors isdisclosed characterized by the premedication of patients prior toradiation therapy. The use of alkyl glycerol ethers concurrently withradiation therapy is also discussed.

This is a continuation of our copending application Ser. No. 530,357filed Feb. 28, 1966, which application is a continuation-impart of ourprior application Ser. No. 392,637 filed Aug. 27, 1964; both priorapplications now abandoned.

This invention is concerned with certain novel pharmaceuticalpreparations and with novel processes for their prophylactic andcurative use. In particular it is concerned with the use of certainhigher alkyl ethers of glycerol and particularly the glycerol ethersknown as batyl, chimyl and selachyl alcohols as well as the glycerolmonoalkyl ether where the alkyl group contains 16 carbon atoms and onedouble bond. The invention also comprises the fatty acid esters of theseglycerol ethers, including monoand di-esters of naturally occuringsaturated or unsaturated acids. These compounds occur in various fishliver oils, particularly in those from the Elasmobranch group. Forinstance the liver oil of the Greenland shark contains ethers with 14-22carbon atoms in the ether side-chain. Both saturated and unsaturatedalcohols are present, selachyl alcohol making up about 60 percent of theether content.

The present invention is based upon the discovery that certain glycerolethers, when adequately administered, have a beneficial influence uponthe body of human and, generally, animal, at least mammal animal beings,in its efforts in protecting itself against and combating various kindsof attacks.

The glycerol ethers contemplated should be a-ethers and preferably havethe general formula CH OH CHOH CH OR wherein R represents an aliphatic,including alicyclic, hydrocarbon radical containing not more than 26carbon atoms, or their physiologically innocuous esters. The radi cal Rshould, of course, be physiologically innocuous or sufficiently nontoxicin the administration forms and quantities contemplated. Of particularinterest are the glycerol ethers wherein the hydrocarbon radicalcontains 14-24 and especially 16 and 18 carbon atoms. The compound or amixture of any two or more thereof may, as a principle, be administeredin a conventional way such as by injection, orally or possibly as anointment. Dosage quantities of active substances will be referred tohereinbelow by mg. per kg. body weight calculated as glycerol ether, theether chain (R) having a molecular weight corresponding to that of batylalcohol.

These glycerol ethers cause an activation and stimula- 3,432,602Patented Mar. 11, 1969 tion of the defence mechanism of a person oranimal treated. Pharmaceutical preparations of such compounds actprophylactically and curatively against exposure to harmful radiation.It has been shown that the survival time after radiation treatment ofcancer is increased.

In cases of leucopenia and thrombocytopenia caused by (radiationtreatment, continuous administration of radiomimetics or cytostatics.) Asignificant increase in leucocyte and thrombocyte counts has beenobtained after treatment with glycerol ethers. In some cases normalvalues for leucocytes and thrombocytes have been found after treatmentfor only one week. Thus the present preparations are useful inprotecting the body, especially the blood-forming tissues, againstharmful side effects and they are consequently of great importance forrestoring or maintaining a normal blood picture.

The survival times for a group of 350 patients suffering from cancer ofthe uterine cervix increase with the total amount of glycerol ethersadministered during the radiation treatment. The increase is observedfor l-year, 5-year and 7-year survivals.

The defence mechanism of the body is effectively stimu- A lated by theadministration of the compounds according to the present invention. Thetheoretical explanation for the observed results is not known withcertainty. It has been shown, however, that the glycerol ethers do notinhibit the growth of microorganisms but on the contrary stimulate thegrowth of for instance lactobacillus lactis. Consequently theantiinfection action of the glycerol ethers is different from that of,for example, antibiotics. Furthermore the effectiveness of the glycerolethers against the effect of harmful radiation suggests a mechanismquite different from that of conventional chemotherapeutic agents, andthat the effects are of a systemic nature. At present one can onlyhazard the guess that defence mechanisms in the organism, notably thereticuloendothelial sys tem, are activated.

For the oral administration the optimum dose varies somewhat and theattending physician in each case will determine the optimum dose for theindividual patient being treated. The optimum dosage as Well as theeffective range of dosage will depend on such variables as the size, ageand sex of the patient or animal, the particular pathological conditioninvolved, and the nature of other prior or concurrent treatment.

In general the effective dose contains from about 0.5 mg. to about 25mg. glycerol ether per kg. body weight per day and especially from25-125 mg. per kg. body weight per day. The dose administered may eitherconsist exclusively of one of said glycerol ethers, or may be a mixtureof any two or more of them. It has been shown that the valuabletherapeutic results mentioned above, especially in the treatment ofleukopenia and thrombocytopenia, caused for example by exposure toharmful radiation, are obtained at a dosage of about 5 mg. per kg. bodyweight per day calculated as glycerol ether which corresponds to about12 mg. of the natural fatty acid esters. This dose causes no sideeffects and is not accompanied by any toxic manifestations. According tothe invention it is possible to use, separately or in mixture,synthetically prepared glycerol ethers, but it is preferable to use amixture of glycerol ethers derived from the liver oils of Elasmobranchfish.

The glycerol ethers or their esters may be used in association with anysuitable well tolerated and physiologically innocuous pharmaceuticaladditives. For instance pharmaceutical compositions may be preparedwhich contain one, two, several or all of the active compounds togetherwith suitable diluents, dispersing and emulsifying agents as well asflavouring agents.

The invention includes within its scope pharmaceutical compositions inthe form of dosage units comprising one or more of the active compoundsand suitable for convenient administration in the dosage quantitieswhich cause the therapeutic effects described above.

Preferably the glycerol ethers and their esters are administered in theform of capsules or tablets containing the active compounds.

EXAMPLE I A concentrate of fatty acid esters of glycerol ethers wasprepared from Greenland shark liver oil. The oil was subjected tomolecular distillation. The residue, containing 28.5% of fatty acidesters of glycerol ethers, was hydrolysed by lipase of Ricinus seeds.The hydrolysis step was followed by further molecular distillation. Thecontent of fatty acid esters of glycerol ethers in the concentrate was59% corresponding to 23.5% of free glycerol ethers.

EXAMPLE II The concentrate of fatty acid esters of glycerol ethers fromGreenland shark liver oil prepared as described in Example I wassubjected to saponification with potassium hydroxide. The unsaponifiablefraction was extracted with ether. After removing the ether, the residuewas deodorized by vacuum steam stripping. The finished product had acontent of 85% (w./w. of free glycerol ethers).

EXAMPLE 111 To produce a suitable pharmaceutical preparation to beadministered drop-wise containing the following ingredients:

g. A mixture of free glycerol ethers derived from Greenland shark liveroil as described in Example 11 containing 85% by weight of free glycerolethers 65 Polyoxyethylene sorbitan monooleate (Tween 80) 2.5 Sorbitanmonooleate (Span 80) 2.5 Peppermint oil 1.8 Anethol 1.4

Ethanol, ad. 100 g.

The dispersing agents and flavouring agents were dissolved in theethanol and this solution was added to the mixture of free glycerolethers.

EXAMPLE IV g. Batyl alcohol, synthetically prepared 65 Tween 80 2.8Peppermint oil 2.2

Ethanol, ad. 100 g.

The ingredients were mixed as described in Example III.

EXAMPLE V g. Batyl alcohol, synthetically prepared 30.0 Chimyl alcohol,synthetically prepared 30.0 Tween 80 3.0 Span 80 3.0 Peppermint oil 1.5Anethol 1.5

Ethanol, ad. 100 g.

The solution was prepared as described in Example III.

EXAMPLE VI g. Selachyl alcohol, synthetically prepared 1,000 Tween 80 30The dispersing agent was added to the selachyl alcohol. The resultingmixture was capsulated. Each capsule containing 103 mg. of the mixture.

4 EXAMPLE v11 A concentrate of fatty acid esters of glycerol ethers fromGreenland shark liver oil as described in Example I with an estercontent corresponding to 23.5% of free glycerol ethers 500 Tween 10 Span80 10 The dispersing agents were added to the concentrate and theresulting mixture was capsulated. Each capsule containing 450 mg. of themixture.

The dispersing agents were added to the concentrate. The anethol wasdissolved in the ethanol and the solution was added to the concentrate.Each capsule containing 270 mg. of the mixture.

EXAMPLE IX A mixture of free glycerol ethers derived from Greenlandshark liver oil as described in Example II containing by weight of freeglycerol ethers 118 Tween 80 3 Span 80 3 Aerosil Lactose 100 Starch 100Gelatin 2 Stearic acid 5 Talcum 7 The oily components were mixed withAerosil, registered trade mark for colloidal silica. From lactose andstarch was made a granulate with gelatin. The components were mixed andtablets were prepared.

The tablets may be coated as with a solution of 30% by weight ofpolyethylen glycol (av. M.V. 6,000) and 15% by weight of polyphenylpyrrolidon in 99.5% ethanol. The solution is added in portions and thetablets are powdered with sugar between each addition. When the tabletshave obtained a weight of 0.55 g. they are coated with an aqueoussolution of 66% by weight of sugar and 3% by weight of gelatin up to aweight of about 0.8 g.

The most interesting aspect of applicants discovery is the fact that theremarkable effect on the bodily defence mechanism seems to depend,generally, on the seemingly slight difference between the molecule of anordinary tri-glyceride and the molecule of a compound identical withthat tri-glyceride but for the carbonyl oxygen of one of the carboxylicacid groups in the tri-glyceride being replaced by hydrogen. One is thusled to believe that in the general formula for the present glycerolethers the composition of the radical R is of little general importanceand may instead be of importance for modifying the effect of thesubstance according to specific indications of bodily irregularities.

It has furthermore been discovered that the survival times of patientssuffering from uterine carvix cancer can be improved significantly byadministering the alkoxyglycerols prophylactically before irradiatingthe patient. Tests have been made on 400 patients treated in one yearaccording to the normal routine with regard to irradiation, i.e. normaldoses of radiation from intracavitory radium application and/or externalX-ray. All patients were treated with alkoxyglycerols in normal doses.These treatments are described in Astrid Brohult, Alkoxyglycerols andtheir use in radiation treatment, Acta Radiologica, 1963. However, in100 of the patients the administration of alkoxyglycerols started 7 daysbefore the irradiation. One year after the treatment of the patientstreated normally had died, while only 9% of the patients treatedprophylactically had died.

What is claimed is:

1. In the process for treating tumors characterized by radiation,radiomimetic or cytostatic treatment, the improvement comprising orallyadministering prior to said treatment an amount of an alkyl glycerolether which is effective to increase the probability of survival and toreduce harmful leucopenia and thrombocytopenia caused by said treatment,said alkyl glycerol ether being at least one member of the groupconsisting of ethers of the formula CH OHCHOHCH OR and physiologicallyinnocuous esters of said ethers where R is selected from the groupconsisting of hydrocarbon radicals with 14 to 24 carbon atoms, saidradical being so selected that said ethers and esters have the chemicalcomposition of alkyl glycerol ethers which occur in the liver oils ofElasmobranch fish.

2. A process according to claim 1 for the treatment of uterine cervixcancer wherein the cancer is treated by radiation, wherein theadministration of said alkyl glycerol ether is commenced approximatelyseven days before radiation.

3. A process according to claim 2 wherein said ethers and esters arederived from the liver oil of Greenland shark.

4. A process according to claim 2 wherein said alkyl glycerol ether isat least one member of the group consisting of chimyl alcohol, batylalcohol and selachyl alcohol, and physiologically innocuous estersthereof.

5. In the process of treating tumors in humans characterized by aregimen of successive radiation treatments, the improvement comprisingorally administering prior to the first of said successive treatments anamount of an alkyl glycerol ether between about 2.5 and 12.5 rug/kg.body weight daily which is effective to increase the probability ofsurvival and to reduce hanmful leucopenia and thrombocytopenia caused bysaid treatment, and continuing said administration until said regimentof successive treatments is completed, said alkyl glycerol ether beingat least one member of the group consisting of ethers of the formula andphysiologically innocuous esters of said ethers, where R is selectedfrom the group consisting of hydrocarbon radicals with 14 to 24 carbonatoms, said radical being so selected that said ethers and esters havethe chemical composition of alkyl glycerol ethers which occur in theliver oils of Elasmobranch fish.

6. A process according to claim 5 wherein the administration of saidalkyl glycerol ether is commenced approximately seven days before thefirst of said successive radiation treatments and administration iscontinued daily until said successive radiation treatments arecompleted.

7. A process according to claim 6 wherein said allcyl glycerol ether isat least one member of the group consisting of chimyl alcohol, batylalcohol, and selachyl alcohol, and physiologically innocuous estersthereof.

References Cited UNITED STATES PATENTS 6/1925 McKee 167-66 OTHERREFERENCES Brohult et al., Nature 174 (4441), 1102-1103, Dec. 11, 1954.

Brohult, A (I) Nature, 181 (4621), 1484-1485, May 24, 1958.

Brohult, A (III) Nature 193 (4822), 1304, Mar. 31, 1962.

Brohult, A (IV) Chem. Abstracts 60 (7) #8326b Mar. 30, 1964.

Brodman et al., Chem. Abstracts 52 #20493i (1958).

Thomas et al., Chem. Abstracts 53 #1518b (1959).

Schultze et al., Chem. Abstracts 53 #15400 (1959).

Ghys. Chem. Abstracts 55 #29302 (1961).

Linman et al., Chem Abstracts 55 #3754d (1961).

Matsui, Chem. Abstracts 55 #7280a (1961).

Hasegawa et al., Chem. Abstracts 56 #4968g (1962).

Bassi et al., Chem Abstracts 57 #4988a (1962).

LEWIS GOTTS, Primary Examiner.

S. K. ROSE, Assistant Examiner.

U.S. Cl. XJR-

